PB1890: TRIAL IN PROGRESS: A PHASE II STUDY OF MIDOSTAURIN COMBINED WITH INDUCTION/CONSOLIDATION CHEMOTHERAPY AND AS SINGLE-AGENT MAINTENANCE IN PEDIATRIC PATENTS WITH FLT3-MUTATED ACUTE MYELOID LEUKEMIA
Authors: Dirk Reinhardt, Michel Zwaan, Dhrubajyoti Pathak, Dawid Sawicki, Lisa Burgmeyer, Muriel Orphee Yokam Tateu, Franco Locatelli
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are common in patients with acute myeloid leukemia (AML) and are often associated with poor outcomes (Daver N, at al. Blood Cancer J. 2021). Midostaurin – an oral, multitargeted tyrosine kinase inhibitor – is approved in several countries, including Europe, where it is indicated for adult patients with newly diagnosed FLT3 mutation-positive (FLT3+) AML in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response as single-agent during maintenance therapy. In Europe, midostaurin is also approved as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (SM), SM with associated hematological neoplasm, or mast-cell leukemia. In pediatric patients with relapsed or refractory AML, single agent midostaurin showed limited efficacy, but its safety profile was consistent with that observed in adult patients (Zwaan CM, et al. Blood 2015). Aims: Here, we describe the study design of a global phase II trial aiming to evaluate the safety, efficacy, and pharmacokinetics of midostaurin plus standard chemotherapy followed by midostaurin maintenance therapy in pediatric patients with newly diagnosed FLT3+ AML (NCT03591510). Methods: This open label, multi-center, single-arm study includes pediatric patients aged 3 months to <18 years with previously untreated AML (per World Health Organization 2016 criteria) and confirmed newly diagnosed FLT3+ (juxtamembrane internal tandem duplication [ITD] and/or mutation in the tyrosine kinase domain [TKD]); patients with concurrent malignancies or secondary AML are excluded. FLT3 status can be determined in a Novartis designated central laboratory or a local laboratory that has successfully passed the Novartis laboratory qualification procedure (currently, there are two Novartis qualified local laboratories: one each in Germany and Italy). The study is composed of 2 parts: part 1, which aimed to determine the recommended phase II dose of midostaurin, has been completed (four patients have been enrolled and treated). Part 2 evaluates midostaurin (30 mg/m² twice daily or 1 mg/kg twice daily for patients <10 kg body weight) in sequential combination with standard chemotherapy, consisting of 2 blocks of remission induction therapy and 3 blocks of consolidation therapy, followed by 12 cycles of single agent midostaurin post-consolidation therapy (Figure 1). The primary objective of part 2 is safety and tolerability. Secondary objectives of part 2 include response rates (complete remission [CR], complete remission with incomplete hematologic recovery [CRi] and modified CRi) at the end of block 2, time to response and response duration, event-free survival, overall survival, disease-free survival, measurable residual disease, and pharmacokinetics. Patients will be followed up for up to 5 years, with an estimated primary study completion date of August 2025, and an estimated study completion date of February 2029. The study is currently enrolling patients in approximately 30 sites worldwide (including 7 countries in the European Union), with a planned sample size of 23 patients (including Part 1 and Part 2) and with an estimated recruitment completion date of February 2024. In Part 2, at least 3 patients will be treated in the safety run-in, followed by enrolment of an additional 17 patients; as of February 27, 2023, 6 patients have been enrolled. Results: None, trial in progress. Summary/Conclusion: None, trial in progress.Keywords: Acute myeloid leukemia, Clinical trial, Pediatric